Chapter 13. Managing Oncologic Emergencies
SECTION A Tumor- and Treatment-Related Complications
Ravinder S. Dhaliwal
KEY POINTS
• Chemotherapy toxicities can be acute or delayed and are potentially life threatening if not appropriately treated.
• Chemotherapy-induced neutropenia is a life-threatening condition when a secondary infection develops. Prompt identification and treatment with broad-spectrum antibiotics is crucial for survival of the patient.
TREATMENT-RELATED COMPLICATIONS
Chemotherapy is widely used in the management of veterinary cancer patients. In addition to the cancer cells, virtually all chemotherapeutic drugs also have an effect on normal replicating cell populations. Rapidly dividing normal cells that are vulnerable to damage include cells of the bone marrow, mucous membranes (including the gastrointestinal [GI] tract), and hair follicles. Current veterinary chemotherapy protocols generally produce minimal toxicity, and side effects are medically manageable. 1-5 It is rare that a patient will experience toxicities necessitating protocol alteration or discontinuation. 6-11 This chapter discusses oncologic emergencies and toxicities associated with chemotherapy and the possible pathogenesis of these complications. Because of their importance, in-depth discussion of drug extravasations is covered in Section B, and the management of nausea and vomiting is covered in Chapter 18, Section A . Radiation-related toxicities are addressed in Chapter 15, Section C .
Drug Hypersensitivity And Anaphylaxis
Type I hypersensitivity reactions can occur with any chemotherapeutic agent. Doxorubicin, l -asparaginase, and paclitaxel (Taxol) are among the most commonly used cytotoxic drugs in veterinary medicine that have a potential for hypersensitivity reactions. 12,13 These reactions characteristically occur during or up to 1 hour after injection. Possible clinical manifestations include urticaria or hives and facial pruritus. Respiratory distress, bronchoconstriction (particularly in cats), vomiting, diarrhea, hematochezia, and circulatory collapse could occur with a systemic anaphylactic reaction. Medical management of an acute hypersensitivity drug reaction is illustrated in Box 13-1 . Most hypersensitivity reactions associated with doxorubicin infusion will rapidly resolve with appropriate intervention, and doxorubicin treatment may be resumed at a slower rate at that point in time. Because of the antigenic nature of l -asparaginase, which is derived from Escherichia coli bacteria, the potential for hypersensitivity reaction increases with each subsequent dose. Premedication with diphenhydramine (2.2 mg/kg SQ) is warranted for animals receiving more than one treatment with this drug. Hypersensitivity reactions are reported to occur in the majority of dogs receiving paclitaxel because of an agent called Cremophor EL, which is present in the drug formulation in order to solubilize the drug. Premedication with prednisone (1 mg/kg PO) 12 to 24 hours before and diphenhydramine (4 mg/kg IM), cimetidine (4 mg/kg IV), and dexamethasone sodium phosphate (2 mg/kg IV) 30 to 60 minutes before paclitaxel administration enabled the use of this agent in dogs 13 with various types of cancer. Regardless of the drug, should an animal exhibit hypersensitivity, they are likely to develop reactions with subsequent doses and pretreatment with diphenhydramine and/or dexamethasone 15 to 20 minutes before the chemotherapy infusion is warranted.
BOX 13-1
MEDICAL MANAGEMENT OF HYPERSENSITIVITY REACTIONS TO CHEMOTHERAPEUTIC AGENTS
1. Discontinue chemotherapy infusion.
2. Ensure that airway is patent.
3. Administer short-acting steroid such as dexamethasone sodium phosphate (0.25–1 mg/kg IV) or methylprednisolone sodium succinate (30 mg/kg IV).
4. Administer diphenhydramine (1 mg/kg IV or 2 mg/kg IM).
5. Administer crystalloid fluids (0.9% sodium chloride, Normosol, lactated Ringer’s solution) at 90 mL/kg/hr in dogs and 44 mL/kg/hr in cats if hypotension occurs.
6. If anaphylactic shock occurs, administer epinephrine (0.01 mL/kg 1:1000 epinephrine IV or IO; 0.2–0.5 mL/kg IM). Administer epinephrine every 15–20 minutes if clinical signs are not resolving.
Hematologic Complications
Neutropenia
Neutropenia is the dose-limiting toxicity of most chemotherapy drugs. The neutrophil nadir (low point in the neutrophil count following chemotherapy administration) is species, patient, and drug specific. For many commonly used drugs, the nadir occurs between 7 and 10 days after treatment. See Table 13-1 for commonly used chemotherapy agents and their expected nadirs. Vincristine (VCR) and l-asparaginase ( l -ASP) as single agents are not typically myelosuppressive at standard dosages. However, one study demonstrated that VCR/ l -ASP in combination were more likely to result in neutropenia than when the drugs were used individually. 14 A grading scheme of hematopoietic toxicity adopted by the Veterinary Cooperative Oncology Group is outlined in Table 13-2 . 15
| Drug | Expected Nadir |
|---|---|
| Cyclophosphamide | 7–10 days |
| Lomustine | 21 days (dogs); 28 days (cats) (can vary significantly) |
| Doxorubicin | 7–10 days |
| Mitoxantrone | 7–10 days |
| Vincristine | 5–7 days |
| Vinblastine | 5–7 days |
| Cisplatin | 7–14 days (double nadir reported in dogs) |
| Carboplatin | 10–14 days |
| ADL , Activities of daily life; LLN , lower limit of normal. | |||||
| Adverse Event | GRADE | ||||
|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | |
| Blood/Bone Marrow | |||||
| Bone marrow cellularity | Mildly hypocellular; <25% reduction from normal cellularity for age | Moderately hypocellular; >25 to <50% reduction from normal cellularity for age | Severely hypocellular; >50% reduction of cellularity from normal for age | — | — |
| Hemoglobin | Dog: g/dl – <LLN Cat: 8.0 g/dl – <LLN | Dog: <10–8.0 g/dl Cat: <8.0–6.5 g/dl | Dog: <8.0–6.5 g/dl Cat: <6.5–5.0 | Dog: <6.5 g/dl Cat: <5.0 | — |
| Neutropenia | 1500/μl – <LLN | 1000-1499/μl | 500-999/μl | <500/μl | — |
| Thrombocytopenia | 100,000/μl – <LLN | 50,000–99,000/μl | 25,000–49,000/μl | <25,000 | — |
| Other (Specify, _________) | Mild | Moderate | Severe | Life-threatening; disabling | Death |
| Gastrointestinal | |||||
| Anorexia | Coaxing or dietary change required to maintain appetite | Oral intake altered (<3 days) without significant weight loss; oral nutritional supplements indicated | Of 3–5 days duration; associated with significant weight loss or malnutrition; IV fluids, tube feeding or TPN indicated | Life-threatening consequences; >5 days duration | Death |
| Colitis | Asymptomatic, pathologic, or radiographic findings only | Abdominal cramping/pain; mucus or blood in stool | Abdominal pain, fever, change in bowel habits, ileus, peritoneal signs | Life-threatening consequences (e.g., perforation, bleeding, ischemia, necrosis) | Death |
| Constipation | Occasional or intermittent symptoms; occasional use of stool softeners, laxatives, dietary modification or enema | Persistent symptoms with regular use of laxatives or enemas indicated | Symptoms interfering with ADL; obstipation with manual evacuation indicated | Life-threatening consequences (e.g., obstruction, megacolon) | Death |
| Dehydration | Increased oral fluids indicated; dry mucous membranes; <skin turgor | Parenteral (IV or SC) fluids indicated <24 hr | IV fluids indicated >24 hr | Life-threatening (e.g., hemodynamic collapse) | Death |
| Diarrhea | Increase of >2 stools per day over baseline | Increase of 2–6 stools per day over baseline; Parenteral (IV or SC) fluids indicated <24 hr; not interfering with ADL | Increase of >6 stools per day over baseline; incontinence; IV fluids >24 hr; hospitalization; interfering with ADL | Life-threatening (e.g., hemodynamic collapse) | Death |
| Gastrointestinal | |||||
| Dysphagia | Symptomatic but able to eat regular diet | Symptomatic and altered eating/swallowing (e.g., altered dietary habits, food consistency); Parenteral (IV or SC) fluids indicated <24 hr | Symptomatic and severely altered eating/swallowing (e.g., inadequate oral caloric or fluid intake); IV fluids >24 hr, tube feeding or PPN/TPN indicated | Life-threatening (e.g., obstruction, perforation) | Death |
| Enteritis (inflammation of the small bowel) | Asymptomatic, pathologic, or radiographic findings only | Abdominal pain/cramping; mucus or blood in stool | Abdominal pain/cramping, fever, change in bowel habits with ileus; peritoneal signs | Life-threatening (e.g., perforation, bleeding, ischemia, necrosis) | Death |
| Flatulence | Mild | Moderate | — | — | — |
| Ileus, GI (functional obstruction of bowel, i.e., neuroconstipation) | Asymptomatic, radiographic finding only | Symptomatic; altered GI function (e.g., altered dietary habits); parenteral (IV or SC) fluids indicated <24 hr | Symptomatic and severely altered GI function; IV fluids, tube feedings, or PPN/TPN indicated >24 hr | Life-threatening consequences | Death |
| Incontinence, anal | Occasional | Daily | Interfering with ADL; operative intervention indicated | Permanent | Death |
| Mucositis/stomatitis | Erythema of the mucosa | Patchy ulcerations or pseudomembranes | Confluent ulcerations or pseudomembranes; bleeding with minor trauma | Tissue necrosis; significant spontaneous bleeding; life-threatening | Death |
| Nausea | Loss of appetite without alteration in eating habits | Salivation or “smacking of lips” <12 hr | Salivation or “smacking of lips” >12–24 hrs | Salivation or “smacking of lips” >24 hr | — |
| Vomiting | <3 episodes in 24 hr | 3–5 episodes in 24 hr; <3 episodes/day for >2 days but <5 days; parenteral (IV or SC) fluids indicated <24 hr | >5 episodes in 24 hr; vomiting >4 days; IV fluids or PPN/TPN indicated >24 hr | Life-threatening (e.g., hemodynamic collapse) | Vomiting |
| Other (Specify, _________) | Mild | Moderate | Severe | Life-threatening | Other (Specify, _________) |
Animals with an absolute neutrophil count of <1000 cells/μl are at risk for developing a secondary infection; however, they will remain asymptomatic unless an infection should develop. Generalized malaise and fever are the two most common clinical signs associated with a secondary infection. The organisms causing infections in cancer patients often come from environmental reservoirs or the host’s own flora and, therefore, are not typically mutated, resistant bacteria. Potential sources of bacterial entry include the GI tract, cutaneous lesions, pre-existing urinary tract infections, and intravenous catheter sites. Unfortunately, neutropenia and GI toxicity frequently occur at similar times, resulting in an increased potential for bacterial translocation across the GI tract wall. Broad-spectrum antibiotics can be chosen based on the presumed origin of the organisms. Generally, cutaneous sources of infection are gram positive, whereas GI tract, urinary tract, and respiratory infections are commonly gram negative in origin.
Because of the risk for neutropenia following chemotherapy administration, a complete blood count (CBC) should be performed the day of treatment (or within 24 hours before the treatment) to ensure an adequate neutrophil count at the time of dosing. In general, treatment should be delayed if the absolute neutrophil count is <3000 cells/μl. The exception to this rule is if the tumor is causing the neutropenia and treatment is necessary for the bone marrow to repopulate. This can occur in stage V lymphoma patients exhibiting myelophthisis (displacement of the bone marrow cells by neoplastic cells). A CBC is also recommended 1 week after treatment, or at the time of the expected neutrophil nadir. If the neutrophil count is <1500 cells/μl on the post-treatment CBC evaluation and the animal is feeling well, broad-spectrum oral antibiotics (e.g., amoxicillin/clavulanic acid or trimethoprim-sulfa) should be initiated to prevent a secondary infection from developing. If the animal is not well or is febrile as well as neutropenic, septicemia should be presumed. This animal should be hospitalized and treated with IV fluid therapy as well as IV broad-spectrum antibiotics (enrofloxacin and ampicillin or cefazolin, ampicillin/sulbactam, or ticarcillin/clavulanic acid). Once the fever has resolved and the animal is feeling well, oral antibiotics can be dispensed if the animal remains neutropenic. Future doses of the specific chemotherapeutic agent resulting in a neutropenia of <500 cells/μl should be decreased by 20% in an attempt to prevent severe neutropenia with subsequent doses. In severely neutropenic patients or patients experiencing a prolonged neutropenia, recombinant human granulocyte colony-stimulating factor (rh-GCSF; Filgrastim; 5 μg/kg SQ daily) 16,17 can be administered to help stimulate granulopoiesis and ameliorate the myelosuppression. 18 It should be noted that evidence of a left shift or degenerative left shift is expected following rh-GCSF administration because of the release of immature granulocytes into the circulation. In addition, this is a human origin product, and antibodies may develop after repeated dosing (usually >20 doses) that can result in prolonged neutropenia. Although septicemia leading to death as a result of chemotherapy is rare, any animal that is not feeling well after chemotherapy should be evaluated immediately with a CBC so that appropriate therapy can be instituted. A few hours delay in treatment may be the difference in survival for septic, neutropenic patients.
Thrombocytopenia
Thrombocytopenia may occur following treatment with chemotherapy drugs but is rarely severe enough to necessitate treatment. Cumulative thrombocytopenia occurs in dogs receiving prolonged CCNU (lomustine) treatment, 19 and thrombocytopenia has also been reported as a common toxicity associated with use of the rescue lymphoma protocol, DMAC (dexamethasone, melphalan, actinomycin D, and cytosine arabinoside). 20
Anemia
Anemia is a common hematologic finding with cancer patients; however, chemotherapy-induced anemia is a rare entity in our experience.
Gastrointestinal Toxicity
Anorexia, vomiting, and diarrhea are the most commonly reported GI toxicities resulting from chemotherapy. 21,22 Box 13-2 shows the relative emetogenic potential of some of the most common chemotherapy drugs used in veterinary oncology. Further information regarding the mechanisms and management of chemotherapy-induced nausea and vomiting can be found in Chapter 18, Section A . Chemotherapy-induced enterocolitis resulting in diarrhea most often occurs with doxorubicin administration, but it can potentially occur with any chemotherapeutic agent. It is generally self-limiting; however, symptomatic treatment may be necessary if diarrhea is severe. Fluid therapy and medications such as loperamide 16 (0.08 mg/kg PO TID; Collie-related breeds may be overly sensitive) or medications containing bismuth subsalicylate 23 (Pepto-Bismol 3–15 ml q8–12 hr; should be used in dogs only) can be used if necessary.
BOX 13-2
EMETOGENIC POTENTIAL OF COMMONLY USED CHEMOTHERAPEUTIC AGENTS
Highly Emetogenic
Cisplatin
Dacarbazine
Doxorubicin
Dactinomycin
Streptozocin
Moderately Emetogenic
Carboplatin
Cyclophosphamide
Procarbazine
Vinorelbine
Mitoxantrone
Mildly Emetogenic
l -Asparaginase
Chlorambucil
Cytarabine
Vincristine
Vinblastine
Melphalan
Fluorouracil
Hydroxyurea
Greater rates of high grade GI toxicity have been reported with 25 mg/m 2 of doxorubicin, when given in combination with cisplatin at 60 mg/m 2 , as adjuvant treatment for canine osteosarcoma. 24 Moore et al. 25 also reported a higher incidence of toxicity with the combination of doxorubicin and vincristine. It appears that small dogs with a mean body weight of 9.9 kg are more likely to have adverse GI effects as a result of carboplatin therapy. 26
Hepatotoxicity
Approximately 6% of dogs developed hepatic toxicity after treatment with oral CCNU in one study. 27 The same study concluded that CCNU could cause delayed, cumulative, dose-related, chronic hepatotoxicity that is irreversible and can be fatal. Serum ALT should be monitored in patients receiving CCNU and the drug discontinued if a four-fold increase above baseline is noted.
Pancreatitis
Pancreatitis is a rare complication of chemotherapy. The drugs commonly associated with pancreatitis include l -asparaginase, azathioprine, and glucocorticoids. 28-30 The mechanism of drug-induced pancreatitis is not known, and the treatment is symptomatic.
Cardiotoxicity
Cardiotoxicity is a well-described adverse effect of doxorubicin in dogs, but it has not been reported in cats. 31-33 It is dose dependent and related to peak plasma concentrations of the drug. Arrhythmias are common during drug administration. The cumulative adverse effects of doxorubicin mimic dilated cardiomyopathy, eventually leading to heart failure. 34 Doxorubicin-associated cardiotoxicity has been reported to occur at cumulative doses as little as 90 mg/m 2 in dogs 35 but is of greater risk in normal dogs at cumulative doses >200 mg/m 2 . 36 Recommendations for total cumulative dose in dogs is between 150 and 240 mg/m 2 . Because of the toxicity also being related to peak plasma concentrations, doxorubicin should be diluted and infused over 30 minutes or longer. Obtaining a baseline echocardiogram to evaluate fractional shortening before beginning doxorubicin treatment and periodically during the treatment protocol should be considered, especially in animals with a predisposition to dilated cardiomyopathy.
Dexrazoxane (Zinecard), an iron-chelating agent, has been shown to reduce the cumulative cardiotoxicity in people and dogs when administered concurrently with doxorubicin. 37,38 In people it is recommended to be given at a ratio of 10:1 (dexrazoxane:doxorubicin) 30 minutes before doxorubicin administration. 39 The dexrazoxane package insert recommends a total elapsed time of 30 minutes from the start of the dexrazoxane infusion to the completion of doxorubicin infusion. A pegylated-liposomal formulation of doxorubicin (Doxil) has been shown to have a reduced risk of causing cardiotoxicity in dogs. 40 The dose-limiting toxicity of Doxil in dogs is palmar-plantar erythrodyesthesia. 41 Unfortunately, the cost of Doxil prohibits its use for many veterinary patients.
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